In 1912, Maillard reported that, when a mixture of amino acid and reducing sugar is heated, it shows brown color (called browning phenomenon). (Maillard, L. C., Compt. Rend. Soc. Biol., 72, 599 (1912)), and suggested that this reaction might occur in a body. In 1968, Rahbar reported that HbAlc, the glycosylated part of haemoglobin (Hg), was increased in diabetics (Rahbar, S., Clin. Chim. Acta., 22, 296 (1968)). Afterwards, it became clean that HbAlc had the chemical structure in which glucose binds to valine in N-terminal side of .beta.-chain in the form of Amadori rearrangement (Koenig, R. J., Blobstein, S. H., & Cerami, A., J. Biol. Chem., 252, 2992 (1977)), and that Maillard reaction proceeds nonenzymatically (Stevens, V. J., Vlassara, H., Abati, A., & Cerami, A., J. Biol. Chem., 252, 2998 (1977)). These results showed that Maillard reaction occurs in a body.
As an initial step, Maillard reaction consists of forming the Amadori rearrangement products by glycosylation of reducing sugar with amino-group of protein. In the advanced stage of this reaction
(1) cross-linked compounds (called advanced glycosylation and products (abbreviated as "AGE")) are produced, PA0 (2) solubility of them becomes low, PA0 (3) the products can not be easily degraded by the action of proteases, PA0 (4) a fluorescent is formed, and then PA0 (5) the products are colored brown. PA0 R.sup.2a is hydrogen, C1-4 alkyl or C1-4 alkoxy; PA0 R.sup.3a is hydrogen, C2-4 acyl or benzoyl; PA0 na is 1-3; PA0 Ya is C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene; PA0 Ma is PA0 Da is PA0 Ba is PA0 Wa is a group of the formula: --W1a--Aa--W2a--; PA0 Aa is PA0 .circle. is C4-10 carbocyclic or heterocyclic ring substituted by one to three C1-4 alkyl, C1-4 alkoxy, halogen, a group of the formula: --COOR.sup.7a, trihalomethyl or acetamido; PA0 W1a and W2a each, independently, is PA0 R.sup.4a is hydrogen or C1-4 alkyl; PA0 R.sup.5a is hydrogen, C1-4 alkyl or amino; PA0 R.sup.6a is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen, a group of the formula: --COOR.sup.8a, trihalomethyl or acetoamido; PA0 R.sup.7a is hydrogen or C1-4 alkyl; PA0 R.sup.8a is hydrogen or C1-4 alkyl; PA0 R.sup.9a is hydrogen, C1-4 alkyl or benzyl; PA0 R.sup.2b is hydrogen, C1-4 alkyl or C1-4 alkoxy; PA0 R.sup.3b is hydrogen, C2-4 acyl or benzoyl; PA0 nb is 1-3; PA0 Yb is C1-7 alkylene, C2-7 alkenylene or C2-7 alkynylene; PA0 Mb is PA0 Db is PA0 Bb is PA0 Wb is a group of the formula: -W1b-Ab-W2b-; PA0 Ab is PA0 .circle. is C4-10 carbocyclic or heterocyclic ring; or C4-10 carbocyclic or heterocyclic ring substituted by one to three C1-4 alkyl, C1-4 alkoxy, halogen, a group of the formula: --COOR.sup.7b, trihalomethyl or acetamido; PA0 W1b and W2b each, independently, is PA0 R.sup.4b is hydrogen or C1-4 alkyl; PA0 R.sup.5b is hydrogen, C1-4 alkyl or amino; PA0 R.sup.6b is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen, a group of the formula: --COOR.sup.8b, trihalomethyl or acetoamido; PA0 R.sup.7b is hydrogen or C1-4 alkyl; PA0 R.sup.8b is hydrogen or C1-4 alkyl; PA0 R.sup.9b is hydrogen, C1-4 alkyl or benzyl; PA0 (i) in an inert organic solvent (methylene chloride, toluene etc.), using dicyclohexylcarbodiimide (DCC) or 2-chloro-1-methylpyridinium iodide or a tertiary amine (triethylamine etc.) at a temperature of from 0.degree. C. to 50.degree. C., PA0 (ii) acid chloride corresponding to acid of the formula (V) with desired amine of the formula (IV) at a temperature of from -10.degree. C. to 40.degree. C. or PA0 (iii) acid of the formula (V) with oxalyl chloride followed by desired amine of the formula (IV) at a temperature of from -20.degree. C. to 0.degree. C. in an inert organic solvent (dimethylformamide (DMF)). PA0 (i) in an inert organic solvent (DMF etc.) in the presence of DCC or a tertiary amine (pyridine, triethylamine etc.), at a temperature of from 0.degree. C. to 50.degree. C., PA0 (ii) acid chloride corresponding to acid of the formula (VII) with desired alcohol of the formula (VI) in an inert organic solvent (DMF etc.), at a temperature of from -10.degree. C. to 40.degree. C., PA0 (iii) acid of the formula (VII) with oxalyl chloride followed by desired alcohol of the formula (VI) at a temperature of from -20.degree. C. to 0.degree. C. in an inert organic solvent (DMF etc.). PA0 (II)-1: the compounds (II)-1, wherein Ma and Za are bond and Wa is bond, C1-8 alkylene, C2-8 alkenylene or alkynylene, are known or may be prepared with using known compounds by known methods and PA0 (II)-2: the compounds (II)-2, wherein Za is --OCO--, may be prepared by the steps shown in scheme 1. ##STR16## (II)-3: The compounds (II)-3, wherein Za is --NR.sup.9a CO--, may be prepared by the steps shown in scheme 2. ##STR17## (II)-4: The compounds (II)-4, wherein Za is--COO--, may be prepared by the steps shwon in scheme 3. ##STR18## (II)-5: The compounds (II)-5, wherein Za is--CONR.sup.9a --, may be prepared by the steps shown in scheme 4. ##STR19## (II)-6: The compounds (II)-6, wherein Za is--O--, may be prepared by the steps shown in scheme 5 and 6. ##STR20## (II)-7: The compounds (II)-7, wherein Za is--NHCONH--, may be prepared by the steps shown in scheme 7-1. ##STR21## (II)-8: The compounds (II)-8, wherein Za is bond; Ma is a group of the formula: --Da--Ba--; and Aa is a group of the formula: ##STR22## may be prepared by the steps shown in scheme 7-2. ##STR23## PA0 (IV)-1: the compounds (IV)-1a, wherein Ma is bond and R.sup.9a is hydrogen, are known or may be prepared with using known compounds by known methods and the compounds (IV)-1b, wherein Ma is bond and R.sup.9a is C1-4 alkyl or benzyl, may be prepared by the steps shown in scheme 9-1. ##STR25## (IV)-2: The compounds (IV)-2, Ma is a group of the formula: --Da--Ba--, may be prepared by the steps shown in scheme 9-2. ##STR26## PA0 (VI)-1: the compounds (VI)-1, wherein Ma is bond, are known or may be prepared with using known compounds by known methods. PA0 (VI)-2: the compounds (VI)-2, wherein Ma is a group of the formula: --Da--Ba--, are prepared by the steps shown in scheme 10. ##STR27## PA0 (VIII)-1: the compounds (VIII)-1, wherein Ma is bond, are known or may be prepared with using known compounds by known methods and PA0 (VIII)-2: the compounds (VIII)-2, wherein Ma is a group of the formula: --Da--Ba--, may be prepared with using CH.sub.3 OCH.sub.2 Cl instead of R.sup.33a Cl used as acylation reagent. PA0 (X)-1: the compounds (X)-1, wherein Ma is bond, are known or may be prepared with using known compounds by known methods and PA0 (X)-2 the compounds (X)-2, wherein Ma is a group of the formula: --Da--Ba--, may be prepared by the steps shown in scheme 11. ##STR28## PA0 (XI)-1: the compounds (XI)-1, wherein Ma is bond, are known or may be prepared with using known compounds by known methods and PA0 (XI)-2: the compounds (XI)-2, wherein Ma is a group of the formula: --Da--Ba--, may be prepared by the steps shown in scheme 12. ##STR29## PA0 R.sup.33a is C2-4 acyl or benzoyl; PA0 R.sup.44a is C1-4 alkyl; PA0 R.sup.31 O is hydroxy or methoxymethoxy; PA0 MOMO is methoxymethoxy; PA0 p-TsCl is p-toluenesulfonyl chloride; PA0 T is tosyl; PA0 R.sup.77 is methyl or ethyl; PA0 Aaa is PA0 DEAD is diethyl azodicarboxylate; and
The mechanism of AGE production has been proposed by some groups. For example, the theory of Brownlee et al is shown below (Brownlee, M. et al., Science, 232, 1629 (1986)). ##STR4##
Maillard reaction is observed in healthy person, and particulary this is caused notably in diabetics that a level of blood sugar is high and in protein of which metabolic turnover is slow.
For example, in the case of haemoglobin, the level of glycosylation in diabetic mouse are 2.7 times as high as that of normal mouse (Monnier, V. M. et al., The Maillard Reaction in Foods and Nutrition, ACS Symposium Series, 215, 432, Am. Chem. Soc., Washington, D.C. (1983)), and glycosylation of serum albumin in diabetics was advanced (Guthrow, C. E. et al., Proc. Natl. Acad. Sci. U.S., 76, 4258 (1979)).
Further, it was turned out that, when a glycosylated serum protein was administrated intravenously during 12 weeks, the typical diabetic renal lesion was observed (Monnier, V. M. et al., Clin. Endocrinol. Metab., 11, 431 (1982)).
Crystallin in lens is the special protein which is not metabolized at all after its biosynthesis. When crystallin was glycosylated, its steric structure was transformed and the SH groups were enzymatically oxidized to form S-S bond. A sequence of processes induced to polymerize the protein in crystallin.
In the case of diabetic cataract in rats, the ratio of binding of protein and glucose was ten times as high as that of normal rat, and also intramolecular S-S bond formation increased (Monnier, V. M. & Cerami, A., Clin. Endocrinol. Metab. 11, 431 (1982)).
Glycosylation of crystallin caused its polymerization, decrease in its solubility, formation of fluorescent substance, and further yellow and brown coloring. This phenomenon is very similar to that of lens by aging (Chiou, S. H., Chylack, L. T., Jr., Tung, W. H., & Bunn, F., J. Biol. Chem., 256, 5176 (1981)).
Collagen and elastin in connective tissue contain lysine and hydroxylysine abundantly, the speed of their metabolic turnover is slow, and the existance of reactants with glucose at the basement membrane of renal adrenal glands, skin and tendon has been found (Monnier, V. M., Stevens, V. J., & Cerami, A., Maillard Reactions in Food, Prog. Food Nutr. Sci., 5, 315, Pergamon Press, London), further these glycosylation products might be related to sclerosis in a blood vessel wall (Rosenburg, H., Modrak, J. B., Hassing, J. M., Al-Turk, W. A., & Stohs, S. J., Biochem. Biophys. Res. Commun, 91, 498 (1979)).
The cause of diabetic neurosis may be nonenzymatic glycosylation of neuro-myelin protein (Monnier, V. M. et al., Clin. Endocrinol. Metab., 11, 431 (1982)).
In this way, Maillard reaction in a body is related to not only various diabetic complication but also a lot of diseases accompanied with aging.
Moreover, in recent research, it is reported that free radical relates to glycosylation of protein. (Diabete & Metabolism (Paris), 14, 25-30 (1988)).